This invention relates generally to CRF receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.
The first corticotropin-releasing factor (CRF) was isolated from ovine hypothalmi and identified as a 41-amino acid peptide (Vale et al., Science 213:1394-1397, 1981). Subsequently, sequences of human and rat CRF were isolated and determined to be identical, but different from ovine CRF in 7 of the 41 amino acid residues (Rivier et al., Proc. Natl. Acad. Sci. USA 80:4851, 1983; Shibahara et al., EMBO J. 2:775, 1983).
CRF has been found to produce profound alterations in endocrine, nervous and immune system function. CRF is believed to be the major physiological regulator of the basal and stress-release of adrenocorticotropic hormone (xe2x80x9cACTHxe2x80x9d), xcex2-endorphin, and other pro-opiomelanocortin (xe2x80x9cPOMCxe2x80x9d)-derived peptides from the anterior pituitary (Vale et al., Science 213:1394-1397, 1981). Briefly, CRF is believed to initiate its biological effects by binding to a plasma membrane receptor which has been found to be distributed throughout the brain (DeSouza et al., Science 224:1449-1451, 1984), pituitary (DeSouza et al., Methods Enzymol. 124:560, 1986; Wynn et al., Biochem. Biophys. Res. Comm. 110:602-608, 1983), adrenals (Udelsman et al., Nature 319:147-150, 1986) and spleen (Webster, E. L., and E. B. DeSouza, Endocrinology 122:609-617, 1988). The CRF receptor is coupled to a GTP-binding protein (Perrin et al., Endocrinology 118:1171-1179, 1986) which mediates CRF-stimulated increase in intracellular production of cAMP (Bilezikjian, L. M., and W. W. Vale, Endocrinology 113:657-662, 1983). The receptor for CRF has now been cloned from rat (Perrin et al., Endo 133(6):3058-3061, 1993), and human brain (Chen et al., PNAS 90(19):8967-8971, 1993; Vita et al., FEBS 335(l):1-5, 1993). This receptor is a 415 amino acid protein comprising seven membrane spanning domains. A comparison of identity between rat and human sequences shows a high degree of homology (97%) at the amino acid level.
In addition to its role in stimulating the production of ACTH and POMC, CRF is also believed to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. Moreover, CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al., J. Clin. Invest. 90:2555-2564, 1992; Sapolsky et al., Science 238:522-524, 1987; Tilders et al., Regul. Peptides 5:77-84, 1982). Overall, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body""s overall response to stress.
Administration of CRF directly to the brain elicits behavioral, physiological, and endocrine responses identical to those observed for an animal exposed to a stressful environment. For example, intracerebroventricular injection of CRF results in behavioral activation (Sutton et al., Nature 297:331, 1982), persistent activation of the electroencephalogram (Ehlers et al., Brain Res. 278:332, 1983), stimulation of the sympathoadrenomedullary pathway (Brown et al., Endocrinology 110:928, 1982), an increase of heart rate and blood pressure (Fisher et al., Endocrinology 110:2222, 1982), an increase in oxygen consumption (Brown et al., Life Sciences 30:207, 1982), alteration of gastrointestinal activity (Williams et al., Am. J. Physiol. 253:G582, 1987), suppression of food consumption (Levine et al., Neuropharmacology 22:337, 1983), modification of sexual behavior (Sirinathsinghji et al., Nature 305:232, 1983), and immune function compromise (Irwin et al., Am. J. Physiol. 255:R744, 1988). Furthermore, clinical data suggests that CRF may be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa. (DeSouza, Ann Reports in Med. Chem. 25:215-223, 1990). Accordingly, clinical data suggests that CRF receptor antagonists may represent novel antidepressant and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
The first CRF receptor antagonists were peptides (see, e.g., Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science 224:889, 1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. For example, substituted 4-thio-5-oxo-3-pyyrazoline derivatives (Abreu et al., U.S. Pat. No. 5,063,245) and substituted 2-aminothiazole derivatives (Courtemanche et al., Australian Patent No. AU-A-41399/93) have been reported as CRF receptor antagonists. These particular derivatives were found to be effective in inhibiting the binding of CRF to its receptor in the 1-10 xcexcM range and 0.1-10 xcexcM range, respectively.
More recently, numerous small molecule CRR receptor antagonists have been proposed, including the compounds disclosed in the following patent documents: WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676, WO 94/13677, WO 95/10506, WO 95/33750, WO 96/35689, WO 97/00868, WO 97,35539, WO 97/35580, WO 97,35846, WO 97/44038, WO 98/03510, WO 98/05661, WO 98/08846, WO 98/08847, WO 98/11075, WO 98/15543, WO 98/21200 and WO 98/29413.
Due to the physiological significance of CRF, the development of biologically-active small molecules having significant CRF receptor binding activity and which are capable of antagonizing the CRF receptor remains a desirable goal. Such CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
While significant strides have been made toward achieving CRF regulation through administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods relating to the use thereof to treat, for example, stress-related disorders. The present invention fulfills these needs, and provides other related advantages.
In brief, this invention is generally directed to CRF receptor antagonists, and more specifically to CRF receptor antagonists having the following general structure (I): 
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, X, R, R1, R2, and Ar are as defined below.
The CRF receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders or illnesses, including stress-related disorders. Such methods include administering an effective amount of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are disclosed containing one or more CRF receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain procedures, compounds and/or compositions, and are hereby incorporated by reference in their entirety.
The present invention is directed generally to compounds useful as corticotropin-releasing factor (CRF) receptor antagonists.
In a first embodiment, the CRF receptor antagonists of this invention have the following structure (I): 
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,
wherein:
n is 1 or 2;
A and C are each independently nitrogen, carbon or CH;
B is nitrogen or CR3;
with the provisos that at least one of A, B and C is nitrogen; A, B and C are not all nitrogen; and either Axe2x80x94B or Bxe2x80x94C is a double bond;
X is nitrogen or CRq;
Rq is hydrogen, alkyl or halo;
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R is an optional substituent which, at each occurrence, is independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the number of R substituents;
R1 is xe2x80x94C(H)0,1(R4)(R5) or xe2x80x94SO2R5;
R2 is hydrogen, alkyl, haloalkyl or cyano;
R3 is hydrogen, alkyl or haloalkyl;
R4 is hydrogen, oxo, alkyl, substituted alkyl, alkylidenyl or halo; and
R5 is a radical of the formula xe2x80x94Yxe2x80x94Zxe2x80x94R6, wherein
Y is an alkanediyl, substituted alkanediyl, or a direct bond,
Z is NH, xe2x80x94N(R7), O, S, SO2, C(xe2x95x90O), C(xe2x95x90O)O, OC(xe2x95x90O), NHC(xe2x95x90O), C(xe2x95x90O)NH, NH(SO2), (SO2)NH, NR8C(xe2x95x90O)O, or a direct bond;
R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl;
R7 and R8 are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring;
or R4 and R5 taken together with the carbon atom to which they are attached form cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle, or substituted cycloalkylheterocycle.
As used herein, the above terms have the following meaning:
xe2x80x9cAlkylxe2x80x9d means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term xe2x80x9clower alkylxe2x80x9d has the same meaning as alkyl but contains from 1 to 6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, xe2x80x94CH2cyclopropyl, xe2x80x94CH2cyclobutyl, xe2x80x94CH2cyclopentyl, xe2x80x94CH2cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls, also referred to as xe2x80x9chomocyclic rings,xe2x80x9d and include di- and poly-homocyclic rings such as decalin and adamantyl. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an xe2x80x9calkenylxe2x80x9d or xe2x80x9calkynylxe2x80x9d, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.
xe2x80x9cAlkylidenylxe2x80x9d represents a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom, such as xe2x95x90CH2, xe2x95x90CHCH3, xe2x95x90CHCH2CH3, xe2x95x90C(CH3)CH2CH3, and the like.
xe2x80x9cAlkanediylxe2x80x9d means a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms, such as xe2x80x94CH2xe2x80x94 xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, and the like.
xe2x80x9cArylxe2x80x9d means an aromatic carbocyclic moiety such as phenyl or naphthyl.
xe2x80x9cArylalkylxe2x80x9d means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, xe2x80x94CH2xe2x80x94(1 or 2-naphthyl), xe2x80x94(CH2)2phenyl, xe2x80x94(CH2)3phenyl, xe2x80x94CH(phenyl)2, and the like.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
xe2x80x9cHeteroarylalkylxe2x80x9d means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as xe2x80x94CH2pyridinyl, xe2x80x94CH2pyrimidinyl, and the like.
xe2x80x9cHeterocyclexe2x80x9d (also referred to herein as a xe2x80x9cheterocycle ringxe2x80x9d) means a 5- to 7-membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
xe2x80x9cHeterocyclealkylxe2x80x9d means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as xe2x80x94CH2morpholinyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated or unsaturated (but not aromatic) carbocyclic ring containing from 3-8 carbon atoms, such as cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the like.
xe2x80x9cCycloalkylcycloalkylxe2x80x9d means a cycloalkyl ring fused to a cycloalkyl ring, such as decalin.
xe2x80x9cCycloalkylarylxe2x80x9d means a cycloalkyl ring fused to aryl, such as tetralin.
xe2x80x9cCycloalkylheterocyclexe2x80x9d means a cycloalkyl ring fused to a heterocycle ring.
The term xe2x80x9csubstitutedxe2x80x9d as used herein means any of the above groups (e.g., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, etc.) wherein at least one hydrogen atom is replaced with a substituent. In the case of a keto substituent (xe2x80x9cxe2x80x94C(xe2x95x90O)xe2x80x94xe2x80x9d) two hydrogen atoms are replaced. When substituted, xe2x80x9csubstituentsxe2x80x9d within the context of this invention include halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, xe2x80x94NRaRb, xe2x80x94NRaC(xe2x95x90O)Rb, xe2x80x94NRaC(xe2x95x90O)NRaNRb, xe2x80x94NRaC(xe2x95x90O)ORb xe2x80x94NRaSO2Rb, ORa, xe2x80x94C(xe2x95x90O)Ra xe2x80x94C(xe2x95x90O)ORa, xe2x80x94C(xe2x95x90O)NRaRb, xe2x80x94OC(xe2x95x90O)NRaRb, xe2x80x94SH, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94S(xe2x95x90O)2Ra, xe2x80x94OS(xe2x95x90O)2Ra, xe2x80x94S(xe2x95x90O)2ORa, wherein Ra and Rb are the same or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocylealkyl or substituted heterocyclealkyl.
xe2x80x9cHalogenxe2x80x9d means fluoro, chloro, bromo and iodo.
xe2x80x9cHaloalkylxe2x80x9d means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl moiety attached through an oxygen bridge (i.e., xe2x80x94O-alkyl) such as methoxy, ethoxy, and the like.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl moiety attached through a sulfur bridge (i.e., xe2x80x94S-alkyl) such as methylthio, ethylthio, and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl moiety attached through a sulfonyl bridge (i.e., xe2x80x94SO2-alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.
xe2x80x9cAlkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d mean one or two alkyl moiety attached through a nitrogen bridge (i.e., xe2x80x94N-alkyl) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl substituted with at least one hydroxyl group.
xe2x80x9cMono- or di(cycloalkyl)methylxe2x80x9d represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
xe2x80x9cAlkylcarbonylalkylxe2x80x9d represents an alkyl substituted with a xe2x80x94C(xe2x95x90O)alkyl group.
xe2x80x9cAlkylcarbonyloxyalkylxe2x80x9d represents an alkyl substituted with a xe2x80x94C(xe2x95x90O)Oalkyl group or a xe2x80x94OC(xe2x95x90O)alkyl group.
xe2x80x9cAlkyloxyalkylxe2x80x9d represents an alkyl substituted with a xe2x80x94O-alkyl group.
xe2x80x9cAlkylthioalkylxe2x80x9d represents a alkyl substituted with a xe2x80x94S-alkyl group.
xe2x80x9cMono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
xe2x80x9cMono- or di(alkyl)aminoalkylxe2x80x9d represents a alkyl substituted with a mono- or di(alkyl)amino.
As used in the context of this invention, 
of structure (I) represents xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 optionally substituted with 1 or 2 R substituents (i.e., when n=1 and m=1 or 2), or xe2x80x94CH2CH2CH2xe2x80x94 optionally substituted with 1, 2 or 3 R substituents (i.e., when n=2 and m=1, 2 or 3). Moieties in this regard are xe2x80x94CH2CH(R)xe2x80x94, xe2x80x94CH(R)CH2xe2x80x94, xe2x80x94CH(R)CH(R)xe2x80x94, xe2x80x94CHxe2x95x90C(R)xe2x80x94, xe2x80x94C(R)xe2x95x90CHxe2x80x94, xe2x80x94C(R)xe2x95x90C(R)xe2x80x94, xe2x80x94CH2CH2CH(R)xe2x80x94, xe2x80x94CH2CH(R)CH2xe2x80x94, xe2x80x94CH(R)CH2CH2xe2x80x94, xe2x80x94CH(R)CH2CH(R), xe2x80x94CH(R)CH(R)CH2 and xe2x80x94CH2CH(R)CH(R)xe2x80x94, wherein each occurrence of R is the same or different and independently selected from the R groups as set forth above.
Thus, representative compounds of this invention include the following structures (Ia) through (In): 
In one embodiment, n is 1 and m is 0 and the CRF receptor antagonists of this invention have structure (Ia). In another embodiment, n is 1 and m is 1 and the CRF receptor antagonists of this invention have structure (Ib) or (Ic).
Depending upon the choice of the A, B and C moieties, the CRF receptor antagonists of this invention include compounds having the following structures (I-1), (I-2), (I-3) and (I-4): 
When X of compounds (I-1), (I-2), (I-3) and (I-4) is CRq, representative compounds of this invention include the following compounds (I-1a), (I-2a), (I-3a), and (I-4a); and when X of compounds (I-1), (I-2), (I-3) and (I-4) is nitrogen, representative compounds of this invention include the following compounds (I-1b), (I-2b), (I-3b) and (I-4b): 
In one embodiment, R1 is xe2x80x94SO2R5, as represented by the following structure: 
In another embodiment, R1 is xe2x80x94C(H)0,1(R4)(R5) which represents both xe2x80x94CH(R4)(R5) and xe2x80x94C(R4)(R5). Representative embodiments in this regard include the following R1 moieties (i), (ii) and (iii): 
Representative R4 moieties of this invention include, but are not limited to, hydrogen, oxo (i.e., xe2x95x90O), halogen (fluoro, chloro, bromo and iodo), methyl, ethyl, n-propyl, n-butyl, n-penty, xe2x95x90CH2, xe2x95x90CHCH3, and xe2x95x90CHCH2CH3. Thus, representative R1 moieties include (but are not limited to) the following: 
In the embodiment where the R4 and R5 groups of R6 taken together form a cycloalkyl, the resulting R1 group has the structure: 
Cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, and the like. Similarly, substituted cycloalkyls are cycloalkyls having one or more substituents as defined above. For example, in one embodiment, the cycloalkyl is substituted with one or more alkyl groups, and representative R1 moieties include the following: 
wherein Rxe2x80x2 and Rxe2x80x3 are the same or different and independently selected from, for example, alkyl such as methyl or ethyl.
In the embodiment where the R4 and R5 groups of R1 taken together form a cycloalkylaryl, and the resulting R1 group include compounds having the structure: 
including optionally substituted analogs thereof as defined above.
In still further embodiments, R4 and R5 are taken together to form a cycloalkylcycloalky or cycloalkylheterocycle, and the resulting R1 group include, for example, compounds having the structure: 
including optionally substituted analogs as defined above.
As noted above, in one embodiment, R5 is a radical of the formula xe2x80x94Yxe2x80x94Zxe2x80x94R6, wherein
Y is an alkanediyl, substituted alkanediyl, or a direct bond,
Z is NH, xe2x80x94N(R7), O, S, SO2, C(xe2x95x90O), C(xe2x95x90O)O, OC(xe2x95x90O), NHC(xe2x95x90O), C(xe2x95x90O)NH, NH(SO2), (SO2)NH, NR8C(xe2x95x90O)O, or a direct bond;
R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
R7 and R8 are the same or different and independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring.
In one embodiment, the R5 moiety has Y as an alkanediyl, Z as a direct bond, and R6 as hydrogen. Such R5 moieties include alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., xe2x80x94CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
In another embodiment, the R5 moiety has Y and Z being direct bonds while R6 includes an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
In another embodiment, the R5 moiety has Y being a direct bond, Z being NH and R6 being as defined above. Thus, R6 may be hydrogen such that R5 is amino. Alternatively, R6 may be alkyl, such that R5 is an alkyl-substituted amino group, e.g., isopropylamino, and ethylamino. Alternatively, R6 may be an aryl or substituted aryl, such that R5 is an arylamino or substituted arylamino group, e.g., (methoxyphenyl)amino, ((trifluoromethoxy)phenyl)amino, (phenyl substituted phenyl)amino (also known as (biphenyl)amino), and (di(trifluoromethyl)phenyl)amino. Alternatively, R6 may be arylalkyl or substituted arylalkyl, such that R5 is an (arylalkyl)amino or (substituted arylalkyl)amino, e.g., (benzyl)amino (also known as (phenylmethyl)amino), (cyclopropylphenyl)amino, and (phenylethyl)amino. Accordingly to this embodiment, a preferred R4 is carbonyl.
In another embodiment, the R5 moiety has Y being alkanediyl, Z being N(R7) and R6 being as defined above, where R7 is also as defined above. Accordingly, R5 is xe2x80x94Yxe2x80x94N(R7)(R6), i.e., includes a disubstituted amino moiety. In one embodiment, Y is methylene, i.e., xe2x80x94CH2xe2x80x94, so that R5 is xe2x80x94CH2xe2x80x94N(R7)(R6). As defined above, R6 and R7 are each selected from alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl, where R6 may additionally be hydrogen. In one embodiment, R6 is hydrogen.
Either one or both of the R6 and R7 groups of xe2x80x94N(R6)(R7) group may be alkyl or substituted alkyl, including saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., xe2x80x94CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
Either one or both of the R6 and R7 groups of xe2x80x94N(R6)(R7) group may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
Thus, xe2x80x94N(R6)(R7) may be, for example, (propyl)(cyclopropylmethyl)amino, (2-cyanoethyl)(methyl)amino, (2-cyanoethyl)(benzyl)amino, (ethyl)((2-(dimethylamino)ethyl))amino, (2-hydroxyethyl)(benzyl)amino, di(2-hydroxyethyl)amino, (propyl)(2-hydoxyethyl)amino, (cyclohexyl)(ethyl)amino, (carboxymethyl)(methyl)amino, di(benzyl)amino, and ((2-hydroxy)(2-phenyl)ethyl))(methyl)amino.
As stated above, R6 and R7 taken together with the nitrogen atom to which they are both attached may form a heterocycle ring or substituted heterocycle ring. Thus, xe2x80x94N(R6)(R7) may represent a heterocycle ring, such as aziridinyl, methyl-substituted aziridinyl, 
A heterocycle, as defined above, may include more heteroatoms (i.e., non-carbon atoms) than the nitrogen of xe2x80x94N(R6)(R7). For instance, the heterocycle may additionally include a second nitrogen, or an oxygen, or a sulfur. When a second nitrogen is present, the heterocycle will have two nitrogens, as in, e.g., piperazinyl. When an oxygen is present, the heterocycle will have both an oxygen and a nitrogen, as in, e.g., morpholinyl. When a sulfur is present, the heterocycle will have both a sulfur and a nitrogen, as in, e.g., thiomorpholinyl. These heterocycles having two or more heteroatoms may be substituted or non-substituted. For instance, the morpholinyl group may be substituted with two alkyl group, e.g., one methyl group on either side of the morpholinyl oxygen atom. When the heterocycle is a piperazinyl group, the nitrogen atom not explicitly shown in the formula xe2x80x94N(R6)(R7) may be substituted, where exemplary substituents are, for example, alkyl (e.g., methyl), substituted alkyl (e.g., 2-hydroxyethyl), or arylalkyl (e.g., benzyl).
In another embodiment, Y is substituted alkanediyl, Z is a heteroatom or a direct bond, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, Y is an alkanediyl having a substituent, where the substituent may be, for example, hydroxy. The alkanediyl may be, for example, ethylene (i.e., xe2x80x94CH2xe2x80x94CH2xe2x80x94), or n-propylene (i.e., xe2x80x94CH2CH2CH2xe2x80x94), such that a substituted alkanediyl may be, e.g., xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94.
In another embodiment, Y is alkanediyl, e.g., methylene (xe2x80x94CH2xe2x80x94), Z is amido, i.e., xe2x80x94NHC(xe2x95x90O)xe2x80x94 or xe2x80x94C(xe2x95x90O)NHxe2x80x94, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, in one embodiment, R5 is xe2x80x94CH2xe2x80x94NHC(xe2x95x90O)xe2x80x94R6.
In another embodiment, Y is alkanediyl, e.g., methylene (xe2x80x94CH2xe2x80x94), Z is sulfonylamido, i.e., xe2x80x94NHSO2xe2x80x94 or xe2x80x94SO2NHxe2x80x94, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, in this embodiment, R5 is xe2x80x94CH2xe2x80x94NHSO2xe2x80x94R6.
In another embodiment, Y and Z are direct bonds and R6 is as defined above. Thus, in this embodiment, R5 is xe2x80x94R6. In one embodiment, R4 is alkyl when R5 is xe2x80x94R6. In another embodiment, R4 is carbonyl when R5 is xe2x80x94R,. The R6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., xe2x80x94CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl. The R6 may be substituted alkyl, where a substituted alkyl may have one, two, or more substituents.
In another embodiment, Y and Z are direct bonds and R6 is as defined above. Thus, in this embodiment, R5 is xe2x80x94R6. In one embodiment, R4 is hydrogen when R5 is xe2x80x94R6. In another embodiment, R4 is alkyl when R5 is xe2x80x94R6.
In another embodiment, Y is a direct bond, Z is an ester group, i.e., xe2x80x94C(xe2x95x90O)Oxe2x80x94 or xe2x80x94OC(xe2x95x90O)xe2x80x94, and R6 is as defined above. In this embodiment, R5 is -ester-R6, and preferably R5 is xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R6. In a one embodiment, R4 is hydrogen. The R6 moiety may be alkyl, preferably lower saturated alkyl, e.g., methyl, ethyl, propyl, etc.
In another embodiment, Y is substituted alkanediyl, Z is a direct bond or oxygen, and R6 is as defined above. In this embodiment, R4 is preferably H. In an alternative embodiment, R4 is preferably alkyl. The alkanediyl may be a C1-C6 alkanediyl, e.g., methylene, ethylene, propylene, etc., and the substituent on the alkanediyl may be, e.g., hydroxy, halogen, amino, alkyl, etc. Accordingly, Y may be xe2x80x94CH(OH)xe2x80x94 or xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, etc. In one embodiment, R6 is aryl or substituted aryl, e.g., phenyl or chlorophenyl. In another embodiment, R6 is alky or substituted alkyl, e.g., methyl or fluoromethyl.
In another embodiment, R1 is SO2R5, where Y is a direct bond, Z is a direct bond, and R6 is as defined above. Accordingly, in this embodiment, R1 is xe2x80x94SO2xe2x80x94R6.
In another embodiment, Y is alkanediyl, Z is O or S, and R6 is as defined above. For example, R5 may be xe2x80x94CH2xe2x80x94Oxe2x80x94CH3 where Y is methylene, Z is O, and R6 is an alkyl, and specifically methyl. In a preferred embodiment, R4 is carbonyl. In another preferred embodiment, R4 is hydrogen. In yet another preferred embodiment, R4 is alkyl.
In another embodiment, Y is a direct bond, Z is a direct bond, and R6 is alkyl or substituted alkyl of the formula xe2x95x90CH2, xe2x95x90CHxe2x80x94CH3, xe2x95x90CHxe2x80x94CH2xe2x80x94CH3, xe2x95x90CHxe2x80x94CH(CH3)xe2x80x94CH3, and homologs thereof The substituent on the substituted alkyl may be, for example, hydroxyl or halogen (e.g., fluoro).
The R6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., xe2x80x94CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
The R6 moiety may be substituted alkyl, where substituted alkyls may have one or may substituents. Suitable substituents include trifluoromethyl, hydroxy, and halogen (i.e., fluoro, chloro, bromo, iodo).
The R6 moiety may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, methoxyphenyl, and chlorophenyl.
The R6 moiety may be heterocycle, heterocyclealkyl, substituted heterocycle, substituted heterocyclealkyl, e.g., furanyl, furanylmethyl, and thienyl, thienymethyl.
In a preferred embodiment, R4 is hydrogen when R5 is xe2x80x94R6 and R6 is alkyl as set forth above. In another embodiment, R4 is alkyl when R5 is xe2x80x94R6 and R6 is alkyl as set forth above. In a preferred embodiment, R4 is hydrogen when R5 is xe2x80x94R6 and R6 includes an aromatic ring as set forth above. In another embodiment, R4 is alkyl when R5 is xe2x80x94R6 and R6 includes an aromatic ring as set forth above.
Representative R1 groups of this invention specifically include each of the R1 groups disclosed in the Examples, as well as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, xe2x80x94CH(ethyl)2, xe2x80x94CH(n-propyl)2, xe2x80x94CH(n-butyl)2, xe2x80x94CH2CH2OCH3, xe2x80x94CH(methyl)(CH2OCH3), xe2x80x94CH(ethyl)(CH2OCH3), xe2x80x94CH(n-propyl)(CH2OCH3), xe2x80x94CH(n-butyl)(CH2OCH3), xe2x80x94CHCxe2x89xa1CH, xe2x80x94CH(methyl)(ethyl), xe2x80x94CH(methyl)(n-propyl), xe2x80x94CH(methyl)(n-butyl), xe2x80x94CH(methyl)(n-pentyl), xe2x80x94CH(methyl)(CH2CH2CH2CH(CH3)2), xe2x80x94CH(ethyl)(n-propyl), xe2x80x94CH(ethyl)(n-butyl), xe2x80x94CH(ethyl)(n-pentyl), xe2x80x94CH(n-propyl)(n-butyl), xe2x80x94CH(n-propyl)(n-pentyl), cyclopropyl, cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1,2,3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl, xe2x80x94CH(methyl)(benzyl), xe2x80x94CH(ethyl)(benzyl), xe2x80x94CH(n-propyl)(benzyl), xe2x80x94CH(n-butyl)(benzyl), xe2x80x94CH2(cyclopropyl), xe2x80x94CH2(cyclobutyl), xe2x80x94CH2CH(methyl)CH2CH3, xe2x80x94CH2CH(ethyl)CH2CH3, xe2x80x94CH2C(CH3)3, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2C(xe2x95x90O)CH2CH3, xe2x80x94C(xe2x95x90O)cyclopropyl, xe2x80x94C(xe2x95x90O)NHbenzyl.
Representative optional R groups of this invention include, when present, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, xe2x95x90CH2, xe2x95x90CHCH3 and phenyl.
In more specific embodiments of this invention, representative Ar groups of this invention include (but are not limited to) the Ar groups identified in the Examples, as well as 2,4-dichlorophenyl, 2,4-dimethyl-phenyl, 2-chloro-4-methylphenyl, 2-methyl-4-chlorophenyl, 2,4,6-trimethylphenyl, 2-chloro-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-trifluoromethyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-trichloromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 4-dimethylamino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl and 4-dimethylamino-pyridin-3-yl.
In another embodiment, compounds of this invention have structure (I) above, wherein R4 is hydrogen, keto, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1 6alkyl, or C1-6alkyloxyC1-6alkyl; R5 is hydrogen, Ar, C1-6alkylAr, OAr, C1-8alkyl, C3-6cycloalkyl, O(C1-8alkyl), mono- or di(C3-6cycloalkyl)methyl, C3-6alkenyl, C3-6alkynyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxyAr, hydroxyC1-6alkyl, thienylC1-6alkyl, furanylC1-6alkyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C1-6alkylAr)amino, (C1-6alkyl)(Ar)amino, C1-6alkylcarbonylC1-6alkyl, sulfonyl(C1-8alky), xe2x80x94C(xe2x95x90O)C1-6alkyl, C1-6alkyl substituted with imidazolyl, or a radical of the formula xe2x80x94(C1-6alkanediyl)xe2x80x94Oxe2x80x94(CO)0.1xe2x80x94Ar; or R4 and R5 taken together form a C3-8cycloalkyl or a C5-8cycloalkyl fused to Ar optionally substituted with one or more substituents independently selected from C1-6alkyl; and Ar is, at each occurrence, independently phenyl or naphthyl, optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, triflouromethyl, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, and mono- or di(C1-6alkyl)amino; or an Garomatic C3-12heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, triflouromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino, and piperidinyl.
The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples, and may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of structure (I) is intended to encompass any and all acceptable salt forms.
In general, the compounds of structure (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples. For example, the synthesis of structure (I) will generally proceed by synthesis of the desired sub-structure (I-1), (I-2), (I-3) or (I-4), as represented below. In turn, synthesis of each of these sub-structures is exemplified in the Examples. 
General Synthesis of Structure (I-1) 
General Synthesis of Structure (I-2) 
General Synthesis of Structure (I-3) 
General Synthesis of Structure (I-4) 
In addition, compounds of structure (I-1) and (I-4) may be made by the following Reaction Scheme A by synthesis of intermediate 4, which is then converted to the corresponding structure (I-1) (structure xe2x80x9c10xe2x80x9d) or (I-4) (structure xe2x80x9c8xe2x80x9d): 
Compounds of structures (I-1) and (I-4) may also be made according to the following Reaction Schemes B and C: 
In addition, compounds of structure (I-1) may be made by the following Reaction Scheme D: 
Further, compounds of structure (I-3) and (I-4) may be prepared by the following Reaction Schemes E and F, respectively: 
The effectiveness of a compound as a CRF receptor antagonist may be determined by various assay methods. Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF. A compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88, 1987) and Battaglia et al. (Synapse 1:572, 1987). As mentioned above, suitable CRF antagonists include compounds which demonstrate CRF receptor affinity. CRF receptor affinity may be determined by binding studies that measure the ability of a compound to inhibit the binding of a radiolabeled CRF (e.g., [125I]tyrosine-CFR) to its receptor (e.g., receptors prepared from rat cerebral cortex membranes). The radioligand binding assay described by DeSouza et al. (supra, 1987) provides an assay for determining a compound""s affinity for the CRF receptor. Such activity is typically calculated from the IC50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the receptor, and is reported as a xe2x80x9cKixe2x80x9d value calculated by the following equation:       K    i    =            IC      50              1      +              L        /                  K          D                    
where L=radioligand and KD=affinity of radioligand for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).
In addition to inhibiting CRF receptor binding, a compound""s CRF receptor antagonist activity may be established by the ability of the compound to antagonize an activity associated with CRF. For example, CRF is known to stimulate various biochemical processes, including adenylate cyclase activity. Therefore, compounds may be evaluated as CRF antagonists by their ability to antagonize CRF-stimulated adenylate cyclase activity by, for example, measuring cAMP levels. The CRF-stimulated adenylate cyclase activity assay described by Battaglia et al. (supra, 1987) provides an assay for determining a compound""s ability to antagonize CRF activity. Accordingly, CRF receptor antagonist activity may be determined by assay techniques which generally include an initial binding assay (such as disclosed by DeSouza (supra, 1987)) followed by a cAMP screening protocol (such as disclosed by Battaglia (supra, 1987)).
With reference to CRF receptor binding affinities, CRF receptor antagonists of this invention have a Ki of less than 10 xcexcM. In a preferred embodiment of this invention, a CRF receptor antagonist has a Ki of less than 1 xcexcM, and more preferably less than 0.25 xcexcM (i.e., 250 nM). As set forth in greater detail below, the Ki values of representative compounds of this invention were assayed by the methods set forth in Example 9. Preferred compounds having a Ki of less than 1 xcexcM are compound numbers I-2a-1 to I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-25, I-2a-27 to I-2a-44, I-2a-46 to I-2a-76, i-2a-92, I-2a-173, I-4b-1 and I-4b-2. More preferred compounds having a Ki of less than 250 nM are compound numbers I-2a-l to I-2a-4, I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-18, I-2a-20 to I-2a-25, I-2a-28 to I-2a-36, I-2a-38 to I-2a-43, I-2a-46 to I-2a-73, I-2a-76, I-4b-1 and I-4b-2.
The CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site, and may be used as therapeutic agents for the treatment of a wide range of disorders or illnesses including endocrine, psychiatric, and neurologic disorders or illnesses. More specifically, the CRF receptor antagonists of the present invention may be useful in treating physiological conditions or disorders arising from the hypersecretion of CRF. Because CRF is believed to be a pivotal neurotransmitter that activates and coordinates the endocrine, behavioral and automatic responses to stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric disorders. Neuropsychiatric disorders which may be treatable by the CRF receptor antagonists of this invention include affective disorders such as depression; anxiety-related disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and feeding disorders such as anorexia nervosa, bulimia, and irritable bowel syndrome. CRF antagonists may also be useful in treating stress-induced immune suppression associated with various diseases states, as well as stroke. Other uses of the CRF antagonists of this invention include treatment of inflammatory conditions (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease and G.I. motility), Cushing""s disease, infantile spasms, epilepsy and other seizures in both infants and adults, and various substance abuse and withdrawal (including alcoholism).
In another embodiment of the invention, pharmaceutical compositions containing one or more CRF receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a CRF receptor antagonist of the present invention (i.e., a compound of structure (I)) and a pharmaceutically acceptable carrier and/or diluent. The CRF receptor antagonist is present in the composition in an amount which is effective to treat a particular disorderxe2x80x94that is, in an amount sufficient to achieve CRF receptor antagonist activity, and preferably with acceptable toxicity to the patient. Preferably, the pharmaceutical compositions of the present invention may include a CRF receptor antagonist in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more preferably from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a CRF receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the CRF receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington""s Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.
In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of an carboxylic acid (xe2x80x94COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.
With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as recemates, reacemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
In another embodiment, the present invention provides a method for treating a variety of disorders or illnesses, including endocrine, psychiatric and neurologic disorders or illnesses. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the disorder or illness. Such methods include systemic administration of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of CRF receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the CRF receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
As mentioned above, administration of a compound of the present invention can be used to treat a wide variety of disorders or illnesses. In particular, the compounds of the present invention may be administered to a warm-blooded animal for the treatment of depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, stroke, inflammation, Cushing""s disease, infantile spasms, epilepsy, and substance abuse or withdrawal.